TAB2

The protein encoded by this gene is an activator of MAP3K7/TAK1, which is required for for the IL-1 induced activation of nuclear factor kappaB and MAPK8/JNK. This protein forms a kinase complex with TRAF6, MAP3K7 and TAB1, and it thus serves as an adaptor that links MAP3K7 and TRAF6. This protein, along with TAB1 and MAP3K7, also participates in the signal transduction induced by TNFSF11/RANKl through the activation of the receptor activator of NF-kappaB (TNFRSF11A/RANK), which may regulate the development and function of osteoclasts. Studies of the related mouse protein indicate that it functions to protect against liver damage caused by chemical stressors. Mutations in this gene cause congenital heart defects, multiple types, 2 (CHTD2). Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]

Full Name

TAB2 TGF-Beta Activated Kinase 1/MAP3K7 Binding Protein 2

Function

Adapter required to activate the JNK and NF-kappa-B signaling pathways through the specific recognition of 'Lys-63'-linked polyubiquitin chains by its RanBP2-type zinc finger (NZF) (PubMed:10882101, PubMed:11460167, PubMed:15327770, PubMed:22158122).
Acts as an adapter linking MAP3K7/TAK1 and TRAF6 to 'Lys-63'-linked polyubiquitin chains (PubMed:10882101, PubMed:11460167, PubMed:15327770, PubMed:22158122).
The RanBP2-type zinc finger (NZF) specifically recognizes Lys-63'-linked polyubiquitin chains unanchored or anchored to the substrate proteins such as RIPK1/RIP1: this acts as a scaffold to organize a large signaling complex to promote autophosphorylation of MAP3K7/TAK1, and subsequent activation of I-kappa-B-kinase (IKK) core complex by MAP3K7/TAK1 (PubMed:15327770, PubMed:22158122).
Regulates the IL1-mediated translocation of NCOR1 out of the nucleus (By similarity).
Involved in heart development (PubMed:20493459).

Biological Process

Heart developmentManual Assertion Based On ExperimentIMP:UniProtKB
Negative regulation of autophagyManual Assertion Based On ExperimentTAS:ParkinsonsUK-UCL
Positive regulation of I-kappaB kinase/NF-kappaB signalingManual Assertion Based On ExperimentIDA:UniProtKB
Positive regulation of protein kinase activityManual Assertion Based On ExperimentIDA:UniProtKB
Response to lipopolysaccharideManual Assertion Based On ExperimentIDA:ARUK-UCL

Cellular Location

Membrane
Endosome membrane
Lysosome membrane
Cytoplasm, cytosol
Following IL1 stimulation, translocation occurs from the membrane to cytosol (PubMed:10882101).
Interaction with TRIM38 promotes translocation from cytosol to endosome and lysosome (PubMed:24434549).

Involvement in disease

Congenital heart defects, multiple types, 2 (CHTD2):
A disease characterized by congenital developmental abnormalities involving structures of the heart. CHTD2 patients have left ventricular outflow tract obstruction, subaortic stenosis, residual aortic regurgitation, atrial fibrillation, bicuspid aortic valve and aortic dilation.

PTM

Degraded in a lysosome-dependent manner following interactiuon with TRIM38.
Ubiquitinated; following IL1 stimulation or TRAF6 overexpression. Ubiquitination involves RBCK1 leading to proteasomal degradation.
Phosphorylated.
(Microbial infection) Methylated at Cys-673 by enteropathogenic E.coli protein NleE or S.flexneri protein OspZ: methylation disrupts zinc-binding and ability to bind 'Lys-63'-linked ubiquitin, leading to NF-kappa-B inactivation.